Search

The resazurin test is one of the most widespread approaches for studying the growth and metabolic activity of microorganisms. It is based on the colour change of the blue indicator, resazurin, to its pink reduced form, resorufin due to the reduction process catalyzed by the metabolic activity. At the same time, the quantitative characterization of the process needs to take into account the fact that one registers the results of the chemical transformation, which can differ from the underlying kinetics of the population growth. Purpose. The principal goal of this work is a sequential modelling of both coupled nonlinear growth processes aimed at obtaining the closed-form solution depending on the specificity and parameters of biological and chemical counterparts and its comparison with the curves obtained experimentally. Methods. The indicator concentration change is derived under the assumption of the logistic bacterial growth catalyzing the unidirectional chemical reaction considered and compared with the photometrically registered growth curve for a population of lactobacteria. Results. It is revealed that the biochemical growth curve will be logistic too only in the case of specially coordinated kinetic parameters and the systems’ carrying capacity. Otherwise, another functional form should be used to approximate the observable dynamics. Conclusion. Thus, the main conclusion consists of drawing attention to the importance of distinguishing between the underlying microbial and observable chemical growth curves. Their difference affects the value of the population growth rate, which is the target of such tests, and, therefore, the proper functional form should be used for the experimental data regression.

Nosocomial pneumonia is one of the most common healthcare-associated infections and the most frequent in intensive care unit (ICU) patients. The clinical and economic consequences of nosocomial pneumonia are very significant, especially for ventilated patients. In this article we present several clinical observations that demonstrate the difficulties of antibacterial therapy of nosocomial pneumonia and ventilator-associated pneumonia in adults in multidisciplinary hospitals in Moscow, which are due to both patient characteristics and profile of circulating pathogens.

Introduction. The issue of the subject of review of cases of compliance of the initiative to hold a referendum on the proposed issue (proposed issues) of the referendum with the Constitution of the Russian Federation by the Constitutional Court of the Russian Federation is not regulated in the federal legislation. In addition, the federal legislation regulates the procedure for considering cases of this category only in general terms. Theoretical analysis. The systematization of the opinions presented in the scientific literature regarding the subject of verification in this category of cases allows us to distinguish two positions: the subject of consideration by the Constitutional Court should include both the issues proposed for a referendum and the entire procedure for the initiative of holding a referendum; only the issues proposed for a referendum should be the subject of consideration by the Constitutional Court. Empirical analysis. The analysis of the criteria (limits) of verification for the category of cases under consideration showed that, in any case, they should include compliance of the issues proposed for a referendum, the division of jurisdiction and powers between the state authorities of the Russian Federation and the state authorities of the constituent entities of the Russian Federation with the Constitution of the Russian Federation. The criteria for the admissibility of the motion, the procedural form and procedural periods of consideration of cases of the category under study need to be improved. Conclusions. The subject of verification in cases of the category under consideration should be not only the issues proposed for a referendum but also the entire procedure for the initiative of holding a referendum. The author proposes to amend the legislation providing for the exemption of the President of the Russian Federation from paying state duty when bringing the matter before the Constitutional Court of the Russian Federation in cases of the category in question, the possibility of participation of representatives of the electoral association or public authority proposing the initiative to hold a referendum, the Central Election Commission of the Russian Federation and the President of the Russian Federation in consideration of cases of this category. The author also proposes to provide a special chapter in the relevant law regulating the consideration of cases of compliance of the initiative to hold a referendum on the proposed issue (proposed issues) of the referendum with the Constitution of the Russian Federation.

Objective. To evaluate prescribing patterns of antimicrobials and quantify them in relation to quality indicators in Russian multi-field hospitals. Materials and Methods. Point Prevalence Survey of Antimicrobial Consumption as a part of an international Global-PPS project was conducted in 8 multi-field hospitals in different Russian cities (Krasnoyarsk, Moscow, Omsk, Saratov, Smolensk, Ulan-Ude, Yakutsk) during the period from May till December 2021. Case records of patients who received therapeutic or prophylactic systemic antimicrobial agents were analyzed. Local practices of antimicrobials’ utilization were evaluated in relation to quality indicators defined by the study protocol. Results. Common mistakes requiring a prompt intervention included low adherence to clinical guidelines, absence of stop/review dates in the medical records, extended duration of surgical prophylaxis, III generation cephalosporin’s overuse and low rate of targeted therapy. Conclusions. The results of the project can be valuable for the improvement to antimicrobial utilization approaches at the study centers as well as for monitoring of antimicrobial stewardship programs’ implementation.

Objective. To perform pharmacoepidemiological analysis of spontaneous reports of adverse drug reactions (ADRs) occurred during macrolide group antibiotics prescription and registered in the “Pharmacovigilance 2.0” subsystem of the Federal Service for Surveillance in Healthcare. Materials and Methods. A retrospective pharmacoepidemiological analysis of spontaneous reports of ADRs arising from the use of all macrolide and azalide antibiotics registered in Russia and registered in the electronic database of the “Pharmacovigilance 2.0” subsystem of the Federal Service for Surveillance in Healthcare for the period from 01.04.2019 to 30.11.2022 was performed. Results. Analysis of the number of spontaneous reports of ADRs, their structure, outcomes and severity criteria was performed. The most clinically significant ADRs were identified, the occurrence of which was reported to pharmacovigilance bodies. The results of a retrospective pharmacoepidemiological analysis showed that the development of complications of pharmacotherapy in most cases was associated with the use of azithromycin and clarithromycin. The main clinical manifestations of adverse drug reactions were skin and subcutaneous tissue disorders, gastrointestinal disorders, as well as general disorders and injection site reactions. Conclusions. It was found that the reported events generally corresponded to the general spectrum of ADRs typical for individual representatives of macrolide and azalide antibiotics.

Diamond color centers have been widely studied in the field of quantum optics. The negatively charged silicon vacancy (SiV−) center exhibits a narrow emission linewidth at the wavelength of 738 nm, a high Debye–Waller factor, and unique spin properties, making it a promising emitter for quantum information technologies, biological imaging, and sensing. In particular, nanodiamond (ND)-based SiV− centers can be heterogeneously integrated with plasmonic and photonic nanostructures and serve as in vivo biomarkers and intracellular thermometers. Out of all methods to produce NDs with SiV− centers, ion implantation offers the unique potential to create controllable numbers of color centers in preselected individual NDs. However, the formation of single color centers in NDs with this technique has not been realized. We report the creation of single SiV− centers featuring stable high-purity single-photon emission through Si implantation into NDs with an average size of ∼20 nm. We observe room temperature emission, with zero-phonon line wavelengths in the range of 730–800 nm and linewidths below 10 nm. Our results offer new opportunities for the controlled production of group-IV diamond color centers with applications in quantum photonics, sensing, and biomedicine.

Objective. To study spectrum of pathogens and the time to colonization of respiratory samples in patients with severe and critical COVID-19 as well as to analyze incidence of nosocomial infections and structure of prescribed antibacterial drugs. Materials and Methods. The prospective observational study included patients aged 18 years and older with confirmed severe and critical COVID-19 from December 2021 to February 2022. During the first 48 hours and then every 2–3 days of hospitalization, a respiratory sample was collected: sputum, tracheal aspirate (if intubated), bronchoalveolar lavage (if bronchoscopy was performed) for microscopy and microbiological examination. Some patients were screened for invasive aspergillosis. Clinical and demographic data, comorbidities, pathogenetic therapy for COVID-19, antibiotic therapy, cases of probable/documented bacterial nosocomial infections, antibiotic-associated diarrhea, and hospital treatment outcomes were recorded. Results. A total of 82 patients were included in this study. Patients with lung parenchyma involvement of more than 50% by computer tomography predominated; most of them (77%) required intubation and mechanical ventilation due to progression of respiratory failure, and 76% of patients had a lethal outcome. During the first 48 hours, a respiratory sample was obtained from 47 patients; the rest of the patients presented with non-productive cough. No growth of microorganisms was detected in 31 (36.8%) cases; clinically significant pathogens were detected in 16 (19.5%) patients. A subsequent analysis included data from 63 patients with a sufficient number of samples for dynamic observation were used. During the first 3 days of ICU stay, the most common bacterial pathogens were Klebsiella pneumoniae without acquired antibiotic resistance and methicillin-susceptible Staphylococcus aureus. From 3rd day and afterwards, an increase in the proportion of Acinetobacter baumannii, other non-fermenting bacteria, and carbapenemresistant Enterobacterales was noted. Among the pathogens causing lower respiratory tract infections, A. baumannii and carbapenem-resistant K. pneumoniae were predominant pathogens and accounted for 76% of cases. Positive galactomannan test results were obtained in 4 cases. Conclusions. The study confirmed importance of bacterial nosocomial infections in patients with severe and critical COVID-19. In the case of the development of nosocomial lower respiratory tract infections, empirical antimicrobial therapy should take into account the predominance of carbapenem-resistant Enterobacteria and A. baumannii, as well as the possibility of invasive aspergillosis.

In order to develop the thinking potential of students, their creative mastering of knowledge, skills and abilities in the chosen professional sphere, the authors of the article consider it necessary to use problem-based training in the educational process. It is the main stimulus for independent cognitive activity of students in the field of research activity. It is difficult for students to work with extensive information. Therefore, the authors have developed and presented in the framework of problem-based training graphic ways of presenting the material in graphical form. They are denotation graphs that make it possible the students to classify and to perceive better the presented information. The authors proposed a binary using of denotation in two subjects: integrated plant protection and foreign language. The article describes the stages of making a denotation graph and its different forms. As a result of the experiment, the authors concluded that binary using of denotation graphs enables students to study the material better and stimulates their studying arousing interest.

The value orientations of students are of great scientific interest from the point of view of the formation of the educational process in universities and are an important subject of sociological and pedagogical research. The aim of our research is to work out a program of value-oriented lessons, connecting the social disciplines as well as curatorial lessons with united axiological topics, apply it in classes with students, evaluate its effectiveness and efficiency to increase the level of knowledge, strengthen motivation to study the values of intercultural communication, elevate axiological orientations of intercultural communication of students to the rank of norm. Our validation tools comprise hypothesis, analysis, observation, synthesis, simulation, mathematical data treatment, experimental tests, and diagnosis methods. During the implementation of the program, the personal and social value groups of the students of the experimental group were most influenced. A positive result of working with the professional values of intercultural communication can be considered a change in their numerical indicators of significance. The strategic direction of the formation of a university student is the motivation for purposeful entry into the system of values as universal socio-cultural orientations. The emphasis shifts to changing personal qualities, which eventually enhance the activity of the individual in the socioprofessional sphere.

Prescribing safe and effective drug therapy is becoming increasingly challenging. Recently, there has been an upward trend in the number of patients experiencing polypragmasy. Thus, according to epidemiological analysis of 180,815 outpatient records in Scotland, 4–9 medications were simultaneously prescribed in 16.9% of cases, 10 or more drugs – in 4.6% of cases. As the number of medications taken by an individual patient increases, so does the likelihood of drug-drug interactions which have clinically important consequences. The number of drug-drug interactions is increasing as new drugs are approved, different metabolic pathways and drug transporters are discovered, and co-prescribing recommendations emerge. This article provides an overview of principles and mechanisms of drug-drug interactions and describes pharmacokinetic and pharmacodynamic interactions associated with antibiotic therapy.

This article describes the study of the link between the students' preference for distance or traditional education and alienation from studying and emotional burnout.Additional variables such as the subjective evaluation of the success of studies, self-control, and academic control were also analysed.An empirical study was conducted on a sample of 359 students using the questionnaire to evaluate 1) preferred forms of education, 2) subjective alienation and burnout for students by E.N.Osin, 3) the scale of academic control by R.Perry and 4) the short scale of self-control by J.Tangney.Data analysis showed that a cautious, rather negative attitude toward distance learning prevailed among students, combined with a preference for traditional and mixed forms of education.Positive correlations were found between the preference for distance learning and alienation and burnout, as well as negative correlations with academic performance, self-control, and academic control.Structural equation modelling confirmed the assumption that the preference for distance learning is directly related to alienation and burnout, as well as indirectly (through burnout and alienation) and inversely related to self-control and academic control.It is concluded that under the conditions of forced distance learning at a university caused by the COVID-19 pandemic, the preference for distance learning is more typical for less successful students experiencing alienation from study and emotional burnout, combined with a lower level of academic control and self-control.

Eric Rytkin,1 Karin Mirzaev,1 Irina Bure,1 Kristina Akmalova,1 Sherzod Abdullaev,1 Anastasiia Kachanova,1 Valery Smirnov,2,3 Elena Grishina,1 Natalia Lyakhova,4 Elena Aleshkovich,4 Anna Saribekian,2 Denis Andreev,2 Alexey Shabunin,4 Dmitry Sychev1 1Institute for Molecular and Personalized Medicine, Russian Medical Academy of Continuous Professional Education, Moscow, Russian Federation; 2Sechenov University, Moscow, Russian Federation; 3NRC Institute of Immunology FMBA of Russia, Moscow, Russian Federation; 4S.P. Botkin City Clinical Hospital, Moscow, Russian FederationCorrespondence: Eric Rytkin Email erytkin@gmail.comAim: The aim of this study is to assess 6 micro-RNAs: miR-126, miR-223, miR-150, miR-29, miR-34, miR-142 as potential biomarkers for P2Y12- inhibitors resistance prediction.Methods: Eighty patients with an acute coronary syndrome undergoing percutaneous coronary intervention treated in a multidisciplinary hospital in Moscow with DAPT (either with ticagrelor, n=45, or clopidogrel, n=35) were enrolled. The carriership of 6 clinically relevant polymorphisms for ticagrelor and 17 for clopidogrel was detected. Expression levels of six prospective miRNAs were measured. The activity of CYP3A4 isoenzyme was measured as the ratio of the concentrations of cortisol and 6β-hydroxycortisol.Results: The polymorphisms of the P2Y12-inhibitors ADME genes that demonstrated statistically significant connection with miRNA expression levels are as follows: P2Y12R (A>G, rs3732759) and miR-29 (p=0.017), miR-34 (p=0.003); CYP2C19*17 (C-806T, rs1224856) and miR-142 (p=0.012); PON1 (Q192R, rs662) and miR-29 (p=0.004), ABCG2 (G>T, rs2231142) and miR-34 (p=0.007). MiRNAs expression levels showed connection with the results of the platelet reactivity assessment by utilizing VerifyNow assay (“Instrumentation laboratory”, MA, US). MiR-126 (β coefficient=− 0.076, SE=0.032, p=0.021), miR-223 (β coefficient=− 0.089, SE=0.041, p=0.032), miR-29 (β coefficient=− 0.042, SE=0.018, p=0.026), miR-142 (β coefficient=− 0.072, SE=0.026, p=0.008) have the potential to be used as biomarkers and may substitute platelet reactivity testing.Conclusion: This study has revealed new biomarkers for P2Y12-inhibitors resistance testing: miR-29, miR-34, miR-126, miR-142, miR-223.Keywords: biomarker, miRNA, polymorphism, acute coronary syndrome, pharmacogenomics

Objectives. The aim was to study the association between moral foundations and Russians’ foreign policy attitudes. Background. There is a growing interest in the factors that determine attitudes towards other peoples and countries, but the foreign policy attitudes of citizens that determine their support of the respective state’s foreign policy remain insufficiently researched. This study examines the foreign policy attitudes in the context of the Moral foundations theory. We assume that militant internationalism is related to binding moral foundations (“Loyalty”, “Respect”, “Purity”) and nationalism, while cooperative internationalism probably is based on the individualizing moral foundations (“Care” and “Justice”). Study design. Correlation design was used, followed by structural linear modeling and analysis of mediation effects. Participants. 214 university students (average age 25.18, 20% men). Measurements. A blank survey was conducted using Moral Foundations Questionnaire by J. Graham et al., the questionnaire developed on the basis of Foreign Policy Attitudes Scales by T. Gravelle et al., and Civil Identity Scale from the International Social Survey. Results. The results of structural equation modeling have confirmed the indirect relation between binding moral foundations and militant internationalism mediated by the nationalism and the direct association between cooperative internationalism and individualizing moral foundations. We also revealed that individualizing moral foundations were inversely associated to nationalism and the related militant internationalism. Conclusions. Russians’ foreign policy attitudes are related with the characteristics of the moral sphere and nationalism: Binding moral foundations indirectly (through nationalism) support militant internationalism, while individualizing moral foundations support cooperative internationalism.

Oleg Balanovsky,1– 3 Valeria Petrushenko,1,4 Karin Mirzaev,2,5 Sherzod Abdullaev,5 Igor Gorin,1,4 Denis Chernevskiy,2 Anastasiya Agdzhoyan,1,2 Elena Balanovska,2,3 Alexander Kryukov,5 Ilyas Temirbulatov,2,5 Dmitriy Sychev5 1Laboratory of Genome Geography, Vavilov Institute of General Genetics, Moscow, Russia; 2Laboratory of Human Population Genetics, Research Centre for Medical Genetics, Moscow, Russia; 3Biobank of North Eurasia, Moscow, Russia; 4Department of Bioinformatics Moscow Institute of Physics and Technology, Moscow, Russia; 5Department of Clinical Pharmacology and Therapeutics, Russian Medical Academy of Continuous Professional Education, Moscow, RussiaCorrespondence: Elena BalanovskaLaboratory of Human Population Genetics, Research Centre for Medical Genetics, Moscow, RussiaTel +7 499 612-81-79Email balanovska@mail.ruDmitriy SychevDepartment of Clinical Pharmacology and Therapeutics, Russian Medical Academy of Continuous Professional Education, Moscow, RussiaTel +7 495 680-05-99Email dmitry.alex.sychev@gmail.comBackground: Information about the distribution of clinically significant genetic markers in different populations may be helpful in elaborating personalized approaches to the clinical management of COVID-19 in the absence of consensus guidelines.Aim: Analyze frequencies and distribution patterns of two markers associated with severe COVID-19 (rs11385942 and rs657152) and look for potential correlations between these markers and deaths from COVID-19 among populations in Russia and across the world.Methods: We genotyped 1883 samples from 91 ethnic groups pooled into 28 populations representing Russia and its neighbor states. We also compiled a dataset on 32 populations from other regions using genotypes extracted or imputed from the available databases. Geographic maps showing the frequency distribution of the analyzed markers were constructed using the obtained data.Results: The cartographic analysis revealed that rs11385942 distribution follows the West Eurasian pattern: the marker is frequent among the populations of Europe, West Asia and South Asia but rare or absent in all other parts of the globe. Notably, the transition from high to low rs11385942 frequencies across Eurasia is not abrupt but follows the clinal variation pattern instead. The distribution of rs657152 is more homogeneous. The analysis of correlations between the frequencies of the studied markers and the epidemiological characteristics of COVID-19 in a population revealed that higher frequencies of both risk alleles correlated positively with mortality from this disease. For rs657152, the correlation was especially strong (r = 0.59, p = 0.02). These reasonable correlations were observed for the “Russian” dataset only: no such correlations were established for the “world” dataset. This could be attributed to the differences in methodology used to collect COVID-19 statistics in different countries.Conclusion: Our findings suggest that genetic differences between populations make a small yet tangible contribution to the heterogeneity of the pandemic worldwide.Keywords: severe COVID-19, genetic markers, AB0, rs11385942, rs657152, gene geography

The study, carried out on a large sample of students (N=820) during the period of forced online learning, made it possible to study the phenomenon of self-moti¬vation of educational activity, and the relationship of its different types with academic success and well-being. The results concerning subjective well-being are largely consistent with the data recently obtained by K. Sheldon and colleagues on American samples, and testify in favor of the importance of internal dialogue with oneself, based on the support of one’s own autonomy. In addition, with the help of structural equation modeling, it was shown that motives of learning activ¬ity are a partial mediator of these relations. Thus, the autonomous strategy of self-motivation is a predictor of the success of students’ learning activities, and this connection is partially mediated by another important source of well-being — the autonomous motivation, represented by internal and identified motivation. On the contrary, a controlled strategy of self-motivation, which presupposes a rigid (“oppressive”) style of self-motivation, was a predictor of the presence of con¬trolled academic motivation, amotivation and an inverse predictor of subjective well-being.

The article deals with the morphosyntactic features of the aspectual category of progressive in K’iche’an languages. The analysis is carried out using methods of intragenetic typology. It is proposed to clarify Vinogradov’s classification of progressive in the Mayan languages in relation to the K’iche’an group. Three types of K’iche’an progressive as well as three strategies for the distribution of ergative–absolutive markers in the progressive are proposed. The boundary between the uniclausal and biclausal analyses of complex aspect constructions in Mayan languages is proposed. The application to K’iche’an languages Robert Dixon’s generalization for aspectually based split ergativity is also described. Three strategies of verb argument marking in the progressive constructions are determined. It was found out that all aspectually conditioned splits in the ergative–absolutive strategy of argument marking in K’iche’an languages are observed in progressive (or historically progressive) constructions.

Objective. Analysis of the relationship between the reasons for pride and shame of the country among young people with different value orientations in Russia. Background. In the last decade, there has been a certain trend towards disagreement in society on key issues of the cultural and political agenda. As a rule, the split is associated with value differences between generations, but differences in values themselves in one generation are not considered. This paper will analyze what causes feelings of pride and shame and how this relates to the values of one of the age categories — youth. Study design. The data obtained as a result of the survey were analyzed using factor and correlation analysis, as well as multidimensional scaling. The structure of reasons for pride and shame among Russian youth is presented, as well as the relationship of the obtained factors with different values. Participants. The sample consisted of 402 Russian students aged 17 to 25 (M=18.6; SD=1), of which 31% were men. Measurements. Russian-language abridged version of Sh. Schwartz’s questionnaire and modified statements about pride and shame from the research of the Levada Center (From 05.09.2016 Levada-Centre has been added to the registry of NPOs that are considered foreign agents). Results. It was found that the reasons for pride formed 4 factors, and the reasons for shame — 5. The resulting factors are differently linked with three values: conservation, openness to change and self-transcendence. The structure of factors and the relationship with values are discussed in detail in the article. Conclusions. The values of conservation, openness to change and self-transcendence are linked to which factors of reason for pride and shame of the country are relevant to young people.

There is a certain lack of of instruments for assessing the relationship between learning outcomes and the teacher’s communication style with students which determines children’s involvement in the learning process and their motivation.The article presents the results of adapting the self-determination theory-based questionnaire, Situations-in-School, for Russian-speaking educational environments on a sample of primary and secondary school teachers (N = 1400) from nine regions of Russia.This questionnaire assesses the four basic styles of teacher-student interaction (autonomy support, structure, control, and chaos) and their subtypes.The results of multidimensional scaling and confirmatory factor analysis indicate that the structure of the questionnaire at the level of items and subscales corresponds to a circular model (circumplex).The presence of eight subscales in the structure of the questionnaire is confirmed by CFA.The correlations of the scales with indicators of resilience and professional self-efficacy indicate construct validity.The questionnaire can be used both for research purposes and in the practice of school psychologists to assess the style of communication between teachers and students.

Objectives. The aim was to study the relationship between moral foundations and intention of voting on the presidential elections in Russia. Background. Voting in political elections is important for consensus of society but a large proportion of voters don’t vote that may depend on psychological characteristics among other factors. There is a growing interest in the world in the moral factors of political preferences and voter turnout due to the elaboration of moral foundations theory. However, the relation between moral sphere and intention to vote as well as possible mediators of this relation remains understudied. Study design. The correlational design with subsequent structural equation modeling was used. The survey was conducted in 2018, 2—6 weeks before the Russian presidential elections. Participants. 126 university students at the age from 18 to 50 years old (80% are women). Measurements. To test these hypotheses we used the Moral foundations questionnaire (by J. Graham et al.), the questionnaire of political engagement elaborated for this research and the questionnaire about intention to vote and some socio-demographic variables. Results. The structural equation modeling showed that binding moral foundations were associated with interest to politics which in turn predicted the intention to vote. We also confirmed the known from the previous researches trend to less intention of voting in youth. Using path analysis we found out that less intention of voting in younger voters was due to their less loyalty and weak interest to politics. Conclusions. The intention of voting on the presidential elections depends on the political engagement related with the binding moral foundations.

DA Sychev,1 OA Baturina,2 KB Mirzaev,1 E Rytkin,1 DV Ivashchenko,1 DA Andreev,2 KA Ryzhikova,1 EA Grishina,1 PO Bochkov,1 RV Shevchenko1 1Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow, Russian Federation; 2Sechenov University, Moscow, Russian FederationCorrespondence: E RytkinRussian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow, Russian FederationEmail erytkin@gmail.comIntroduction: The aim of this study is to assess the influence of gene CYP2C19, CYP3A4, CYP3A5 and ABCB1 polymorphisms on clopidogrel antiplatelet activity, rivaroxaban concentration equilibrium, and clinical outcomes among patients with acute coronary syndrome and non-valvular atrial fibrillation.Methods: In the multicenter prospective registry study of the efficacy and safety of a combined antithrombotic therapy 103 patients with non-valvular atrial fibrillation both undergoing or not a percutaneous coronary intervention were enrolled. The trial assessed the primary outcomes (major bleeding, in-hospital death, cardiovascular death, stroke ransient ischaemic attack, death/renal insufficiency) and secondary outcomes (platelet reactivity units (PRU), rivaroxaban concentration).Results: For none of the clinical outcomes when combined with other covariates, the carriership of polymorphisms CYP3A5*3 rs776746, CYP2C19*2 rs4244285;*17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738 was significant. None of the markers under study (CYP3A5*3 rs776746, CYP2C19*2 rs4244285, *17 rs12248560, ABCB1 3435 C>T, ABCB1 rs4148738) has proven to affect rivaroxaban equilibrium concentration in blood plasma among patients with atrial fibrillation and acute coronary syndrome.Conclusion: In situations of double or triple antithrombotic rivaroxaban and clopidogrel therapy among patients with atrial fibrillation and acute coronary syndrome, the genetic factors associated with bleeding complications risk (CYP2C19*17) may prove to be clinically relevant.Keywords: rivaroxaban, clopidogrel, polymorphism, atrial fibrillation, acute coronary syndrome

A study was made of the possibility of using lupine flour, produced from the seeds of blue lupine and white lupine, in the production of pasta. The possibility of using lupine flour in an amount of up to 15% by weight of durum wheat flour for pasta of the highest grade has been established in order to enrich pasta with biologically valuable nutrients without a noticeable deterioration in physicochemical and organoleptic indicators.

Using the PCR-RFLP method, we genotyped pigs for the genes GBP1 (mutation c. [10A>G; 11A>G]), FUT1 (mutation G307A) and MUC4(A243G) associated with resistance to infectious diseases. A total of 188 boars of four breeds (Duroc, Large White, Landrace and Yorkshire) from the Belgorod Region of Russian Federation were studied. The highest frequency of favorable genotype AG for the polymorphism GBP1E2, which is resistant to pig respiratory syndrome, was characterized by the Duroc breed (0.38). The highest frequency of Eischerichia coli F18-resistant AA genotype was observed in the Landrace population (0.19). And in terms of resistance to E. coli with fibrium type F4 (K 88), the highest frequency of favorable genotype GG is characterized by the breed Large White (0,23). In general, it can be noted that genetic resistance in the studied boars is observed predominantly only to one infectious disease.

The search for new effective strains-producers of enzymes and biologically active substances for the development of new environmentally friendly plant protection products against phytopathogens is a very urgent task for the greening of agriculture. In our work, we used active strains of gram-positive spore-forming bacteria isolated from soil near the roadside zone of the Belgorod region to assess their antagonistic activity to phytopathogens and biotechnological potential. In the course of molecular genetic studies of the 16S rRNA gene of the isolated native strain, a complete similarity of the target with Bacillus subtilis was revealed. When studying morphological and cultural characteristics, it was determined that the cells of the target strain are rod-shaped, arranged singly or in pairs.The conditions of cultivation of the bacterium were revealed, which shows high growth in the composition of the medium containing 3% peptone for 20 hours, the specific increase in biomass exceeded 96%. When evaluating the antagonistic activity, it was revealed that the isolated strain suppresses the growth of cultures of Escherichia coli O157:H7, Aspergillus unguis VKM F-1754 and bacteria of the genus Ralstonia.

Margarita N Dorofeeva,1 Evgenia V Shikh,2 Zhanna M Sizova,1 Alisa V Tarasenko,3 Natalia P Denisenko,4,5 Valeriy V Smirnov,6,7 Kristina A Ryzhikova,4 Zhannet A Sozaeva,4 Elena A Grishina,4 Dmitriy A Sychev5 1Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Propedeutics of Internal Diseases, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 3Medicine of the Future, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Research Institute, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 5Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 6Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov university), Ministry of Healthcare, Moscow, Russia; 7Laboratory of Clinical Pharmacology, National Research Centre - Institute of Immunology, Federal Medical Biological Agency, Moscow, RussiaCorrespondence: Natalia P DenisenkoResearch Institute, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Barrikadnaja Street, 2/1, Moscow 125993, RussiaTel +7 495 945 81 39Email natalypilipenko3990@gmail.comBackground: CYP2C19 and CYP3A are the main enzymes involved in omeprazole metabolism, while CYP3A is the principal enzyme family for amlodipine biotransformation. Concomitant use of these drugs in patients with hypertension and acid-related disorders (ARD) might lead to drug–drug interaction.Purpose: The aim of the study was to find if adding omeprazole for treating ARD to amlodipine long-term therapy of hypertension influenced blood pressure of CYP2C19 polymorphism carriers.Patients and methods: Fifty-one patients diagnosed with hypertension and ARD were enrolled in the study. Evaluation of antihypertensive therapy was performed by office (OBPM) and ambulatory (ABPM) blood pressure monitoring. Peripheral venous blood was collected for DNA extraction and real-time polymerase chain reaction was performed for CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C−806T (rs12248560) polymorphisms analysis.Results: Of 51 patients there were 21 extensive metabolizers (EMs), 18 ultrarapid metabolizers (UMs) and 12 intermediate metabolizers (IMs). The results of OBPM showed that antihypertensive effect was significantly more pronounced in IMs compared to EMs or UMs and the average group value in the following parameters: average office systolic blood pressure (BP), dynamics of the average office systolic BP. According to dynamics of diastolic BP, the antihypertensive effect was also significantly higher in IMs than in UMs and the average group value. The results of ABPM revealed that there was a significantly more pronounced antihypertensive effect in IMs compared to all other analyzed groups according to the dynamics of both daytime systolic and 24 hr diastolic BP. The average daytime diastolic BP and its dynamics, the average 24 hr systolic BP and its dynamics were higher in IMs compared to EMs and UMs.Conclusion: Adding omeprazole to long-term amlodipine therapy in patients with hypertension and ARD may lead to a significantly more pronounced antihypertensive effect in patients genotyped CYP2C19 IMs.Keywords: CYP2C19, CYP3A, pharmacogenetics, proton pump inhibitor

M S Zastrozhin,1,2 V Yu Skryabin,1 S S Miroshkin,1,2 E A Bryun,1,2 D A Sychev1,21Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Moscow 109390, Russian Federation; 2Department of Addictology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow 123995, Russian FederationAbstract: Genetics of alcohol addiction is currently a contradictive and complex field, where data in the most studies reflect methods’ limitations rather than meaningful and complementary results. In our review, we focus on the genetics of alcohol addiction, leaving genetics of acute alcohol intoxication out of the scope. A review of the literature on pharmacogenetic biomarkers development for the pharmacotherapy personalization reveals that today the evidence base concerning these biomarkers is still insufficient. In particular, now the researches with the design of randomized controlled trials and meta-analysis investigating the effect of the SNPs as biomarkers on the therapy efficacy are available for naltrexone only. For other medications, there are only a few studies in small samples. It decreases the possibilities to implement the pharmacogenetic algorithms for the pharmacotherapy personalization in patients with alcohol use disorders (AUD). In view of the importance of the precision approaches development not in addiction medicine only, but in other fields of medicine also to increase the efficacy and safety of the therapy, studies on pharmacogenetic biomarkers development for the medications used in patients with AUD (eg, naltrexone, disulfiram, nalmefene, acamprosate, etc.) remain relevant to this day.Keywords: pharmacogenetics, pharmacogenomics, alcohol use disorder, naltrexone, acamprosate, nalmefene

The goals of modern education go beyond mastering cognitive skills, competencies and knowledge. An equally important result of education is the child's school well-being, his/her positive attitude towards school, learning, teachers, and his/her own potential. This study is dedicated to the exploration of internal and external predictors of well-being in Russian elementary schoolchildren (N=1006).It assesses the impact of the learning system (developmental/traditional), satisfaction with relationships with teachers, and intrinsic and extrinsic types of academic motivation on school well-being and academic self-esteem. The results of the study show that the well-being of elementary schoolchildren is based on the positive impact of intrinsic and autonomous motivation and the negative impact of external motivation based on control and demands of teachers and parents. The results also show that the child’s relationship with the teacher and perception of him/her as an interesting person, ready to help and support in the learning process, play an important role in the child’s school well-being and intrinsic motivation. The results of structural equation modeling (SEM) confirm that developmental education programs, in comparison with traditional ones, also contribute to school well-being and academic self-esteem of elementary schoolchildren. The practical significance of the study is to take into account the role of both pedagogical (the role of the teacher’s personality and the teaching system) and psychological factors (intrinsic and extrinsic motivation) in maintaining the well-being of elementary schoolchildren.

The article presents results of developing the Multidimensional Students’ Life Satisfaction Scale for primary school children based on MSLSS by E.S.Huebner.The questionnaire involves five scales: Family, School, Teachers, Myself, Friends as well as an overall index of life satisfaction.The reliability and validity of the questionnaire are demonstrated on the sample of primary school children (third and fourth grades, N=483).Five factor structure is confirmed by the results of confirmatory factor analysis.All the scales have high reliability (0.82 < α < 0.89) and show expected correlations with other indicators of subjective well-being and different scales of self-esteem (as assessed by Dembo-Rubinstein technique).The article contains the text of the questionnaire and normative data for primary school children.

Dmitry Sychev,1 Nadezhda Shikh,2 Tatiana Morozova,2 Elena Grishina,3 Kristina Ryzhikova,3 Elena Malova1 1Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Pharmacotherapy, Institute of Professional Education, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia; 3Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia Purpose: The aim of this study was to determine the impact of ABCB1 (MDR1) rs1045642 polymorphisms on the efficacy and safety of amlodipine in Caucasian patients. Patients and methods: The 12-week study included 100 patients. Patients with the newly diagnosed stage I–II hypertension (HT) were recruited to complete genotyping of the rs1045642 single-nucleotide polymorphism (SNP). The study design did not include a control group. Before treatment, all patients either did not undergo antihypertensive treatment at all or did not receive regular antihypertensive therapy. The initial dose was 5 mg/day. Four office blood pressure measurements, two 24-hour noninvasive ambulatory blood pressure measurements, and questionnaires of Tsvetov were used to evaluate the efficacy and safety of amlodipine. Results and conclusion: The highest antihypertensive effect in combination with the lowest incidence of adverse reactions was observed in the TT group, while patients with the CC genotype showed a low antihypertensive effect and the highest incidence of adverse effects. Patients with the CC genotype presented with adverse effects predominantly in the form of edema. A total of 33 patients reached the target blood pressure (SBP

Dmitriy Alekseevich Sychev,1 Alexander Nikolaevich Levanov,2 Tatiana Vladimirovna Shelekhova,2 Pavel Olegovich Bochkov,3 Natalia Pavlovna Denisenko,4 Kristina Anatolyevna Ryzhikova,4 Karin Badavievich Mirzaev,3 Elena Anatolyevna Grishina,4 Mikhail Alekseevich Gavrilov,5 Galina Vladislavovna Ramenskaya,6 Aleksei Vladimirovich Kozlov,6 Tanya Bogoslovsky7 1Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 2Department of Occupational Pathology, Haematology and Clinical Pharmacology, Saratov State Medical University named after V.I. Razumovsky, Saratov, Russia; 3Department of Personalized Medicine, Research Center, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 4Department of Molecular Medicine, Research Center, Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 5Department of Traumatology and Orthopedics, Research Institute of Traumatology, Orthopedics and Neurosurgery, Saratov State Medical University named after V.I. Razumovsky, Saratov, Russia; 6Department of A.P. Arzamastsev Pharmaceutical and Toxicological Chemistry, Sechenov First Moscow Medical State University, Moscow, Russia; 7Department of Neurology, Division of Clinical Neurosciences, Turku University Hospital, Turku, Finland Background: Non-vitamin K oral anticoagulants (NOACs) are commonly used for prophylaxis of venous thromboembolism (VTE) in orthopedic patients. Despite known safety and high potency of NOACs, potential interactions of NOACs with genetic polymorphisms are poorly understood. Dabigatran etexilate is one of the most commonly prescribed direct thrombin inhibitors for the prevention of VTE. The objectives of this study were to assess the effect of ABCB1 (rs1045642 and rs4148738) and CES1 (rs2244613) polymorphisms on dabigatran pharmacokinetics in patients after total knee arthroplasty. Patients and methods: A total of 60 patients, aged 37–81 years, who underwent surgery for knee replacement have been included in the study. VTE prophylaxis was conducted via administration of dabigatran etexilate 220 mg once daily. Genotyping for carrier state of polymorphic variants such as rs1045642 and rs4148738 of the ABCB1 gene and rs2244613 of the CES1 gene was carried out using real-time polymerase chain reaction (PCR). We also measured the peak and trough concentrations of plasma dabigatran by using high-performance liquid chromatography (HPLC). Results: Our study revealed that TT genotype of rs1045642 polymorphism of the ABCB1 gene was associated with higher dabigatran equilibrium peak concentrations and the higher risk of bleeding than the presence of CC genotype (p

The modern trends in the field of food quality management place emphasis on ensuring the traceability and systemic control of the parameters of the life cycle of products. ISO 9000 international standards recommend a process approach for these purposes. Since the standards do not give direct recommendations on the procedure for estimating the effectiveness of the quality management system (QMS), the development of approaches is an extremely urgent task for developers and has a wide application value. The given paper proposes a mathematical model for the complex estimation of the effectiveness of the QMS of a food enterprise. At the first stage, IDEF0 functional modeling methods were used to identify the processes of the life cycle of food products. Then, using the qualimetric approach, 27 unique indices were generated and coefficients were determined for each of them using Fishburn's weight coefficients. To derive a mathematical model for the complex estimation of the effectiveness of QMS processes of a food enterprise, all data were summarized from four levels of the hierarchy. The proposed mathematical model includes the quantitative and qualitative estimation of enterprise processes. The estimation indicators form a treelike hierarchy in which the factors of each sublevel have their own weight coefficients and are in preference or indifference relation to each other. The application of a mathematical model for the complex estimation of the effectiveness of QMS of a food or processing enterprise allows full compliance with the requirements of international standards, but does not require significant financial costs for implementation.

Natalia P Denisenko,1–3 Dmitriy A Sychev,2 Zhanna M Sizova,3 Valeriy V Smirnov,4,5 Kristina A Ryzhikova,1 Zhannet A Sozaeva,1 Elena A Grishina1 1Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 3Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 5Laboratory of Clinical Pharmacology, National Research Centre – Institute of Immunology, Federal Medical Biological Agency, Moscow, Russia Background: Proton pump inhibitors (PPIs) are metabolized by cytochrome P450. CYP2C19 is the main isoenzyme for the majority of PPI, whereas CYP3A family is a secondary enzyme for PPI biotransformation. Purpose: The aim of the study was to find if CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*3, and CYP2C19*17 genotypes are connected with CYP3A and CYP2C19 activities in Russian peptic ulcer patients taking omeprazole. Patients and methods: Forty-eight gastric or duodenal ulcer patients (15 men, 33 women; mean age 55.0±15.3 years, age range 18–91 years) from Moscow region of Russia were enrolled. Peripheral venous blood was collected for DNA extraction, and real-time polymerase chain reaction was performed for CYP3A5*3 A6986G (rs776746), CYP3A4*22 C>T in intron 6 (rs35599367), CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893), and CYP2C19*17C-806T (rs12248560) polymorphism analyses. Urine samples of patients were collected in the morning between 6 and 9 am before food or drug intake. Urine cortisol and 6β-hydroxycortisol concentrations (for CYP3A activity) and omeprazole and 5-hydroxyomeprazole concentrations (for CYP2C19 activity) were measured using high-performance liquid chromatography/mass spectroscopy. Results: We found a connection between CYP2C19 genotypes and CYP3A activity. Median metabolic ratios 6β-hydroxycortisol/cortisol (25%–75% percentiles) were 2.84 (1.99–4.39) for CYP2C19 extensive metabolizers (EMs), 2.51 (1.86–4.73) for CYP2C19 ultra-rapid metabolizers (UMs), and 1.45 (1.12–2.16) for CYP2C19 intermediate metabolizers (IMs) + poor metabolizers (PMs). A statistically significant difference in CYP3A activity (Mann–Whitney test) was found between CYP2C19 EMs vs CYP2C19 IMs+PMs (p=0.006), between CYP2C19 UMs vs CYP2C19 IMs+PMs (p=0.018), and in multiple comparison Kruskal–Wallis test (p=0.014). Conclusion: In CYP2C19 IMs+PMs, CYP3A activity was significantly lower than in CYP2C19 EMs and UMs. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

Mikhail Sergeevich Zastrozhin,1,2 Elena Anatolievna Grishina,3 Nataliya Petrovna Denisenko,3 Valentin Yurievich Skryabin,2 Dmitry Dmitrievich Markov,3 Ludmila Mikhailovna Savchenko,1 Evgeny Alekseevich Bryun,1,2 Dmitry Alekseevich Sychev4 1Department of Addictology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russia; 2Department of Addictology, Moscow Research and Practical Center on Addictions, Moscow, Russia; 3Research Centre, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Research Centre, Moscow, Russia; 4Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russia Background: Fluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose-dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis. Objective: The primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose-dependent undesirable side effects and pharmacoresistance. Methods: The study involved 45 male patients (average age: 36.44±9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real-time polymerase chain reaction. Results: According to results of Mann–Whitney U-test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (PA polymorphic marker. Keywords: pharmacogenetics, SSRIs, fluvoxamine, biotransformation, personalized medicine, CYP2D6, depressive disorders, alcohol addiction

Dmitrij A Sychev,1 Ghulam Md Ashraf,2 Andrey A Svistunov,3 Maksim L Maksimov,4 Vadim V Tarasov,3 Vladimir N Chubarev,3 Vitalij A Otdelenov,1 Natal’ja P Denisenko,1 George E Barreto,5,6 Gjumrakch Aliev7–9 1Russian Medical Academy of Postgraduate Education Studies, Moscow, Russia; 2King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; 3Sechenov First Moscow State Medical University, Moscow, Russia; 4Branch Campus of the Federal State Budgetary Educational Institution of Further Professional Education «Russian Medical Academy of Continuous Professional Education» of the Ministry of Healthcare of the Russian Federation, Kazan State Medical Academy, Volga Region, Kazan, Russia; 5Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; 6Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile; 7GALLY International Biomedical Research Consulting LLC, San Antonio, TX, USA; 8School of Health Science and Healthcare Administration, University of Atlanta, Johns Creek, GA, USA; 9Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, Russia Abstract: Cytochrome (CYP) 450 isoenzymes are the basic enzymes involved in Phase I biotransformation. The most important role in biotransformation belongs to CYP3A4, CYP2D6, CYP2C9, CYP2C19 and CYP1A2. Inhibition and induction of CYP isoenzymes caused by drugs are important and clinically relevant pharmacokinetic mechanisms of drug interaction. Investigation of the activity of CYP isoenzymes by using phenotyping methods (such as the determination of the concentration of specific substrates and metabolites in biological fluids) during drug administration provides the prediction of negative side effects caused by drug interaction. In clinical practice, the process of phenotyping of CYP isoenzymes and some endogenous substrates in the ratio of cortisol to 6β-hydroxycortisol in urine for the evaluation of CYP3A4 activity has been deemed to be a quite promising, safe and minimally invasive method for patients nowadays. Keywords: cytochrome CYP450, drug interaction, drug metabolism, phenotyping

Alexander Valerevich Kryukov,1 Dmitry Alekseevich Sychev,1 Denis Anatolevich Andreev,2 Kristina Anatolievna Ryzhikova,1 Elena Anatolievna Grishina,1 Anastasia Vladislavovna Ryabova,1 Mark Alekseevich Loskutnikov,3 Valeriy Valerevich Smirnov,4 Olga Dmitrievna Konova,1 Irina Andreevna Matsneva,2 Pavel Olegovich Bochkov1 1Russian Medical Academy of Continuous Professional Education, Moscow, Russia; 2Department of General Medicine, Sechenov First Moscow State Medical University, Moscow, Russia; 3L.A. Vorohobov City Clinical Hospital, Moscow, Russia; 4NRC Institute of Immunology FMBA of Russia, Moscow, Russia Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-β-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent. Results: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A. Conclusion: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class. Keywords: cardioembolic stroke, atrial fibrillation, non-vitamin K anticoagulants, apixaban, pharmacokinetics, pharmacogenetics

Background. Traditional ideas about the fluid circulation in the lens assume its movement through the lens capsule inside-out and its surface distribution in the lens bulk. It is alleged that "fresh" intraocular fluid directionally diffuses from the posterior chambera into the lens toward its center through both its the anterior capsul epithelium and the posterior lens capsule wall. Then intraocular fluid moves along the lamillar structures of the lens towards the equator, where, likely, the Na+, K+-pump activity is maximal. Removal of "waste" of fluid from the lens bag goes in all directions: either through the anterior and posterior capsule, or through the equatorial part. However, these views do not take into account the physiological characteristics of the transport properties of the anterior capsule epithelium that is capable, due to an existing therein ion exchange system, to provide only the one-way fluid flow: from outside to inside. The possible changes in the level of pressure within the lens in different accommodation phases, which may affect the intensity or direction of water exchange, are also not taken into account. The aim of the research. To identify the main mechanisms of the water-exchange process in the lenses of animals, taking into account a phase of accommodation. Materials and Methods. Lenses of rabbits and cattle were studied. The fluid transport processes in the lenses were examined in vitro by changing their weight when placed in incubatory solutions with or without an inhibitor of Na+, K+ -ATPase. In the first part of the in vitro studies, the lens partially (some lenses with the anterior surface, others with posterior surface) were immersed in solutions representing the lens surrounding medium. In the second part of the in vitro study, the lenses were completely immersed in a solution similar in ionic composition to aqueous humor, with different osmotic pressures. The direction of movement of intraocular fluid was studied in vivo according to dye distribution using biomicroscopy and a stopped diffusion method. Results. The epithelium of the anterior lens capsule of rabbits and cattle supports the water transport from the posterior chamber of the eye into the lens through the work of Na+, K+ -ATPase. This active ion transport system facilitates the directed movement of the "fresh" fluid, rich in metabolites, through the anterior capsular epithelium from the anterior surface of the lens capsule to the posterior one. For the first time we found that at the completely "near" accommodation phase the maximal pressure inside the lens capsule is 6 mm Hg. This state is a dynamic balance for the lens, i.e. the value of the osmotic pressure of 6 mm Hg balances in the lens the level of the mechanical pressure of the capsule. The lens weight right after removing was close to its original weight with the osmotic pressure of 6 mm Hg. When looking completely "far", the lens bag is stretched with a ciliary zonule and minimally compresses the masses inside the lens (minimal intracranial pressure). This contributes to the intensive inflow into the lens of "fresh" fluid. The anterior capsular epithelium of the lens was found to support the water transport from the posterior chamber of the eye into the lens by the active ion transport system Na+, K+ -ATPase. It is important to note that the fluid circulation inside the lens occurs along the osmotic gradient and is always unidirectional from its anterior epithelium to the posterior wall of the capsule. Diffusive fluid circulation inside the lens does not occur through its nucleus, but along the fibers inside the lens, followed by diffusion of the "waste" fluid outward through the posterior surface of the lens into the vitreous chamber. This mechanism of micro changes in the volume and/or fluid replacement in the lens can be thought of as a mechanism of "fluctuations" of the lens volume. Conclusion. The theory of "lens volume fluctuations" at the "near-far" accommodation phases is presented; the theory is confirmed in animal experiments in vivo and in vitro. Understanding this physiological process makes it possible to selectively choose the type of rational correction for more effective inhibition and prevention of the cataract or presbyopic process.

Mikhail Sergeevich Zastrozhin,1,2 Elena Anatolievna Grishina,1 Kristina Anatolievna Ryzhikova,1 Valery Valerievich Smirnov,3 Ludmila Mikhailovna Savchenko,1 Evgeny Alekseevich Bryun,1,2 Dmitry Alekseevich Sychev1 1Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, 2Moscow Research and Practical Centre on Addictions, Moscow Department of Healthcare, 3National Research Center Institute of Immunology, Federal Medical-Biological Agency, Moscow, Russia Background: Isoenzymes CYP2D6 and CYP3A4, the activity of which varies widely, are involved in metabolism of haloperidol and may influence its profile of efficacy and safety.Objective: The primary aim of this study was to estimate the relationship between CYP3A5 gene polymorphism, activity of the CYP3A isoenzyme, and the risk of development of adverse drug reactions by haloperidol in patients with alcohol abuse.Methods: Sixty-six male alcohol-addicted patients participated in the study. The safety of haloperidol was evaluated by Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and Simpson–Angus Scale for extrapyramidal symptoms (SAS). The activity of CYP3A was evaluated by determining the concentrations of an endogenous substrate of this isoenzyme (cortisol) and its urinary metabolite (6-beta-hydroxycortisol, 6-B-HC). Genotyping of CYP3A5*3 was performed by real-time polymerase chain reaction with allele-specific hybridization.Results: The frequency of A-allele occurrence in Russian population was very poor (2.27%). CYP3A5*3 polymorphism had no influence on safety profile indicators of haloperidol (UKU scale: p=0.55, SAS scale: p=0.64). In addition, there was no statistical significant difference between the values of indexes of the metabolic ratio (6-B-HC/cortisol) in groups with different genotypes of CYP3A5*3: GG 5.00 (3.36; 6.39) vs AG 5.26 (2.10; 6.78) (p=0.902).Conclusion: The frequency of A-allele occurrence of CYP3A5*3 in Russian population is very poor, and it has no high influence on the safety of haloperidol treatment; therefore, there are no reasons to take this polymorphism into account in patients with alcohol addiction who receive haloperidol. Keywords: haloperidol, CYP3A5*, CYP3A, cortisol, alcohol use disorder

Natalia P Denisenko,1–3 Dmitriy A Sychev,2 Zhanna M Sizova,3 Valeriy V Smirnov,4,5 Kristina A Ryzhikova,1 Zhannet A Sozaeva,1 Elena A Grishina1 1Research Center, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 2Department of Clinical Pharmacology and Therapy, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, Moscow, Russia; 3Department of Social Expertise, Urgent and Outpatient Therapy, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 4Department of Pharmaceutical and Toxicological Chemistry, First Moscow State Medical University (Sechenov University), Ministry of Healthcare, Moscow, Russia; 5Laboratory of Clinical Pharmacology, National Research Centre, Institute of Immunology, Federal Medical Biological Agency, Moscow, Russia Background: CYP2C19 is known to be the main enzyme of biotransformation of proton pump inhibitors (PPIs), whereas the CYP2C19 gene is highly polymorphic. Genotyping and phenotyping together represent more reliable data about patient’s CYP2C19 activity.Purpose: The aim of the study was to investigate the applicability of urine metabolic ratio of omeprazole for CYP2C19 phenotyping in Russian peptic ulcer patients with different CYP2C19 genotypes.Patients and methods: A total of 59 patients (19 men and 40 women) aged 18–91 years (mean age 53.5±15.1 years) from four Moscow clinics who were diagnosed with an endoscopically and histologically proven peptic ulcer or had a history of endoscopically and histologically proven ulcers in the past were recruited. Peripheral venous blood (6 mL) was collected for DNA extraction, and real-time polymerase chain reaction was performed for the analysis of CYP2C19*2G681A (rs4244285), CYP2C19*3G636A (rs4986893) and CYP2C19*17C-806T (rs12248560) polymorphisms. Urine samples of patients were collected in the morning between 6 am and 9 am, before food or drug intake, after at least 3 days of twice daily (b.i.d.) omeprazole intake. Omeprazole and 5-hydroxyomeprazole concentrations in the urine were measured using high-performance liquid chromatography with mass spectrometry.Results: Of the 59 patients, there were 27 (45.8%) extensive metabolizers (EMs; CYP2C19*1/*1), 16 (27.1%) ultrarapid metabolizers (UMs; CYP2C19*1/*17, CYP2C19*17/*17), 14 (23.7%) intermediate metabolizers (IMs; CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*3/*17) and two (3.4%) poor metabolizers (PMs; CYP2C19*2/*2). Median metabolic ratio (25%–75% percentiles) were 1.03 (0.69–1.36) for EMs, 1.95 (1.33–2.68) for UMs, 1.40 (0.78–2.13) for IMs+PMs and 1.26 (0.82–1.99) for the whole sample. A statistically significant difference in metabolic ratio (Mann–Whitney U test) was found between UMs and EMs (p=0.001) and in the multiple comparison Kruskal–Wallis test (p=0.005).Conclusion: We found a connection between particular CYP2C19 genotypes and urine metabolic ratio of omeprazole in Russian peptic ulcer patients. This method needs to be improved as in our modification it worked mainly for UMs and did not differentiate all patients according to omeprazole biotransformation activity. Keywords: pharmacogenetics, phenotyping, metabolomics, proton pump inhibitor

People differ significantly in how they usually explain to themselves the reasons of events, both positive and negative, that happen in their lives. Psychological research shows that children who tend to think optimistically have certain advantages as compared to their pessimistically thinking peers: they are less likely to suffer from depression, establish more positive relationships with peers, and demonstrate higher academic achievements. This paper describes the process of creating the children’s version of the Optimistic Attributional Style Questionnaire (OASQ-C). This technique is based on the theory of learned hopelessness and optimism developed by M. Seligman, L. Abramson and J. Teas dale and is an efficient (compact) tool for measuring optimism as an explanatory style in children and adolescents (9-14 years). Confirmatory factor analysis revealed that this technique is a two-factor structure with acceptable reliability. Validity is supported by the presence of expected correlations between explanatory style and rates of psychological well-being, dispositional optimism, positive attitude to life and its aspects, depression, and academic performance. The outcomes of this technique are not affected by social desirability. The developed questionnaire may be recommended to researchers and school counsellors for evaluating optimism (optimistic thinking) as one of the major factors in psychological well-being of children; it may also be used in assessing the effectiveness of cognitive oriented training for adolescents.

Mikhail Sergeevich Zastrozhin,1,2 Vadim Markovich Brodyansky,3 Valentin Yurievich Skryabin,4 Elena Anatolievna Grishina,5 Dmitry Vladimirovich Ivashchenko,5 Kristina Anatolievna Ryzhikova,5 Ludmila Mikhaylovna Savchenko,1 Alexander Olegovich Kibitov,3 Evgeny Alekseevich Bryun,1,4 Dmitry Alekseevich Sychev6 1Department of Addictology, Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Moscow, Russia; 2Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Center for the Prevention of Dependent Behavior, Moscow, Russia; 3Federal Medical Research Centre of Psychiatry and Addictology, Laboratory of Molecular Genetics, Moscow, Russia; 4Moscow Research and Practical Centre on Addictions of the Moscow Department of Healthcare, Department of Addictology, Moscow, Russia; 5Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Research Centre, Moscow, Russia; 6Russian Medical Academy of Continuous Professional Education of the Ministry of Health of the Russian Federation, Department of Clinical Pharmacology and Therapy, Moscow, Russia Background: Antipsychotic action of haloperidol is due to blockade of D2 receptors in the mesolimbic dopamine pathway, while the adverse drug reactions are associated with striatal D2 receptor blockade. Contradictory data concerning the effects of genetic polymorphisms of genes encoding these receptors and associated structures (catechol-O-methyltransferase [COMT], glycine transporter and gene encoding the density of D2 receptors on the neuronal membrane) are described.Objective: The objectives of this study were to evaluate the correlation between DRD2, SLC6A3 (DAT) and COMT genetic polymorphisms and to investigate their effect on the development of adverse drug reactions in patients with alcohol-use disorder who received haloperidol.Patients and methods: The study included 64 male patients (average age 41.38 ± 10.14 years, median age 40 years, lower quintile [LQ] 35 years, upper quintile [UQ] 49 years). Bio-Rad CFX Manager™ software and “SNP-Screen” sets of “Syntol” (Russia) were used to determine polymorphisms rs4680, rs1800497, rs1124493, rs2242592, rs2298826 and rs2863170. In every “SNP-Screen” set, two allele-specific hybridizations were used, which allowed to determine two alleles of studied polymorphism separately on two fluorescence channels.Results: Results of this study detected a statistically significant difference in the adverse drug reaction intensity in patients receiving haloperidol with genotypes 9/10 and 10/10 of polymorphic marker SLC6A3 rs28363170. In patients receiving haloperidol in tablets, the increases in the UKU Side-Effect Rating Scale (UKU) score of 9.96 ± 2.24 (10/10) versus 13 ± 2.37 (9/10; p

Karin B Mirzaev,1 Elena M Zelenskaya,2 Olga L Barbarash,3 Vladimir I Ganyukov,3 Konstantin A Apartsin,4,5 Natalya O Saraeva,4 Konstantin Y Nikolaev,6,7 Kristina A Ryzhikova,1 Galina I Lifshits,2,5,7 Dmitry A Sychev1 1Russian Medical Academy of Continuous Professional Education, Ministry of Health of the Russian Federation, Moscow, 2Federal State-Financed Research Institution “Institute of Chemical Biology and Fundamental Medicine”, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 3Federal State-Financed Research Institution “Research Institute for Complex Issues of Cardiovascular Diseases”, Siberian Branch of the Russian Academy of Sciences, Kemerovo, 4State-Financed Health Institution “Irkutsk Regional Badge of Honour Clinical Hospital”, 5Federal State-Financed Research Institution “Irkutsk Research Center”, Siberian Branch of the Russian Academy of Sciences, Irkutsk City, 6Federal State-Financed Research Institution “Research Institute of Internal and Preventive Medicine”, 7Federal State Autonomous Institution of Higher Education “Novosibirsk National Research State University”, Novosibirsk, Russia Purpose: The aim of this study is to investigate the frequency of CYP2C19*2, *3 allelic variants, associated with poor response to clopidogrel, and CYP2C19*17, associated with excessive response to clopidogrel, in patients with acute coronary syndrome (ACS) from Siberia and Moscow regions of Russia.Patients and methods: The study included 512 ACS patients who were subsequently treated with coronary arterial stenting. The subjects assigned were from the cities of Central (Novosibirsk, Kemerovo), Eastern (Irkutsk), Northern (Surgut) Siberia regions and from Moscow region. The mean age of patients enrolled was 63.9±10.9 years. Among the assigned subjects, the proportion of men accounted for 80% and women 20%.Results: According to the results obtained in the present study, from 16% up to 27.5% of patients in different regions of Russia have at least one CYP2C19 “poor metabolizer” (PM) allele variant affecting clopidogrel metabolism and, therefore, suppressing its antiplatelet activity. CYP2C19*17 allele variant was identified with the frequency of 15.4% up to 33.3%. The study revealed the presence of statistically significant differences in CYP2C19*3 allele frequency between the Russian ethnic group patients from Eastern and Central Siberia (p=0.001; odds ratio=1.05 [95% confidence interval 1.01–1.09]).Conclusion: The study revealed statistically significant differences between the allele frequencies in Eastern and Central Siberia, which can probably be caused by a considerable number of Buryats inhabiting Eastern Siberia. Keywords: P2Y12 receptor inhibitors, clopidogrel resistance, dual antiplatelet therapy

Dmitrij Alekseevitch Sychev,1 Grigorij Nikolaevich Shuev,1 Salavat Shejhovich Suleymanov,2 Kristina Anatol’evna Ryzhikova,3 Karin Badavievich Mirzaev,3 Elena Anatol’evna Grishina,3 Natalia Evgenievna Snalina,3 Zhannet Alimovna Sozaeva,3 Anton Mikhailovich Grabuzdov,4 Irina Andreevna Matsneva4 1Department of Internal Medicine and Clinical Pharmacology, Russian Medical Academy of Continuing Professional Education, Ministry of Healthcare, Moscow, 2Saiko Russian–Japanese Medical Center, Khabarovsk, 3Research Centre, Russian Medical Academy of Continuous Professional Education, Ministry of Healthcare, 4Department of General Medicine, Sechenov First Moscow State Medical University, Moscow, Russian Federation Background: The efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency. Materials and methods: We studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data. Results: After performing the real-time polymerase chain reactions on the samples from 70 healthy volunteers from the Nanai group, for the CYP2C9*2C430T polymorphism we determined 70 CC-genotype carriers. As for the CYP2C9*3A1075C polymorphism, we found 62 AA-genotype carriers and eight AC-genotype carriers. For the CYP2C19*2G681A polymorphism, we determined 39 GG-genotype carriers and 28 GA-genotype carriers, for the CYP2C19*3G636A polymorphism 58 GG-genotype carriers and 12 GA-genotype carriers, and for the CYP2C19*17C806T polymorphism 67 CC-genotype carriers and three CT-genotype carriers. For the CYP2D6*4G1846A polymorphism, the GG genotype had 68 carriers, and the GA genotype two carriers. For the ABCB1*6C3435T polymorphism, there were 19 CC-genotype carriers and 39 CT-genotype carriers. For the SLCO1B1*5T521C polymorphism, the TT genotype had 41 carriers and the CT genotype 25 carriers. The distribution of genotypes fitted the Hardy–Weinberg equilibrium for all the polymorphisms, except those of CYP2C9*2. There were also significant differences in allele frequencies for some polymorphisms between the Nanais and the Russians. Conclusion: In the Nanai population, there are polymorphisms connected with the decrease in safety and efficiency of drug therapy. Studying the ethnic differences might influence the determination of priority in the introduction of pharmacogenetic tests in clinical practice in different regions of Russia. Keywords: pharmacogenetics, ethnicity, Asians, Europeans, SNP, P450 cytochrome, ethnic group, P-glycoprotein

Relationship satisfaction may be considered as a general assessment based on the emotional experience in marital relationships. The results of theoretical analysis show that the main and direct reason of negative emotions in relationships is frustration of psychological needs. Satisfaction of these needs in spouses’ life is connected with individual differences in attachment and love. Based on these ideas we suggested hypothesis that connection of attachment style with relationship satisfaction is explained by frustration of basic psychological needs of people with insecure attachment style. To check this hypothesis we tested 68 couples, 30 of them were married and 38 cohabited. Relationship satisfaction measured using RAS by Hendrick highly correlated with basic needs satisfaction (measured using Need satisfaction scale by La Guardia) and attachment style (measured using the Russian version of ECR by Sabel'nikova and Kashirskii). The results of structural equation modeling led to the conclusion that negative association of anxious attachment with relationship satisfaction was totally explained by frustration of basic needs (first of all, need for relatedness) while the negative effect of avoidant attachment was accounted for frustration partially. Also it was shown that people with